Aspirin formulation for cardiovascular health

ABSTRACT

The invention relates generally to an aspirin formulation which may comprise additional vitamins, minerals, herbs and supplements and methods for using the same for maintaining cardiovascular health. The aspirin formulation may comprise supplements such as vitamin B6, vitamin B12, folic acid, arginine and garlic. The invention also encompasses methods for maintaining healthy blood pressure and cholesterol levels with the aspirin formulation described herein.

INCORPORATION BY REFERENCE

This application is a continuation of U.S patent application Ser. No.11/323,093 filed Dec. 30, 2005. Reference is also made to U.S patentapplication Ser. No. 11/323,091 filed Dec. 30, 2005.

The foregoing applications, and all documents cited therein or duringtheir prosecution (“appln cited documents”) and all documents cited orreferenced herein (“herein cited documents”), and all documents cited orreferenced in herein cited documents, together with any manufacturer'sinstructions, descriptions, product specifications, and product sheetsfor any products mentioned herein or in any document incorporated byreference herein, are hereby incorporated herein by reference, and maybe employed in the practice of the invention. Reference is also made tocopending application Ser. No. To Be Assigned (attorney docket no.870052-2003.1C) filed Mar. 19, 2007.

FIELD OF THE INVENTION

The invention relates generally to an aspirin formulation which maycomprise additional vitamins, minerals, herbs and supplements andmethods for using the same for maintaining cardiovascular health.

BACKGROUND OF THE INVENTION

Cardiovascular disease is the leading cause of death in the UnitedStates and many other countries. Nutritional factors are widelyrecognized as playing a role in preventing, delaying the onset of and/orslowing the progression of arteriosclerosis and coronary heart disease.

Most risk markers for cardiovascular disease have a pro-inflammatorycomponent, which stimulates the release of a number of active moleculessuch as inflammatory mediators, reactive oxygen species, nitric oxide,and peroxynitrite from endothelial, vascular smooth muscle, and immunecells in response to injury (reviewed by Osiecki, Altern Med Rev. 2004March; 9(1): 32-53). Nutrients such as arginine, antioxidants (vitaminsC and E, lipoic acid, glutathione), and enzyme cofactors (vitamins B2and B3, folate, and tetrahydrobiopterin) help to elevate nitric oxidelevels and may play an important role in the management ofcardiovascular disease. Other dietary components such as DHA/EPA fromfish oil, tocotrienols, vitamins B6 and B12, and quercetin contributefurther to mitigating the inflammatory process.

Aspirin has a role in the prevention of cardiovascular andcerebrovascular disease, Alzheimer's dementia and several cancers.Encouraging all 50 year olds to take low-dose aspirin doubles theirchances of living a healthy life into their nineties. The widespread useof aspirin, however, is limited as many older subjects are currentlyunable to take aspirin because of gastrointestinal side-effects. Areview by Newton et al. (Aliment Pharmacol Ther. 2004 Jan.1;19(1):39-45) explores why gastrointestinal events occur with aspirinuse and how a net benefit from prophylactic aspirin might be achieved inolder subjects. It is suggested that, by understanding the age-relatedchanges in upper gastrointestinal physiology and the mechanisms by whichaspirin leads to the risk reductions associated with its use, it may bepossible to direct interventions to improve tolerability in oldersubjects.

Aspirin (acetylsalicylic acid), the most widely used antiplatelet drug,is clinically effective for the prevention of vascular ischaemic events(reviewed by Mahe et al. Drugs Aging. 2003;20(13):999-1010). Very fewprimary or secondary prevention trials address the benefit-risk ratio ofaspirin in the elderly. In secondary prevention, it is generallyaccepted that the beneficial effect of aspirin in the general patientpopulation, demonstrated by randomised controlled trials, can beextrapolated to the elderly. Elderly patients are at relatively highrisk for the development of vascular disease and might also be expectedto derive substantial benefit from regular aspirin administration.Retrospective studies in the elderly found that the benefit provided byaspirin in older patients was similar or increased compared with youngerindividuals. In primary prevention, the potential benefit ofantiplatelet agents must be balanced against the risk of bleeding, whichis higher in older patients.

The gastro-intestinal (GI) toxicity associated with high dose aspirinhas been fully demonstrated, but remains poorly elucidated at low dosesi.e., less than 500 mg/day (reviewed by Sibilia et al., Presse Med. 2003Nov. 22;32(37 Pt 2):S17-28). Such toxicity is relatively difficult tostudy because lesional and/or bleeding GI complications are not alwayswell described in studies. The GI risk exists, starting with the lowestdoses and appears to be dose-dependent. The lesional complicationsconsist mainly of erosive lesions, most often gastric, and rarely trueulcers. Cases of bleeding appear more frequent, but generally are minor.

Low-dose aspirin is an important therapeutic option in the prevention ofcardiovascular disease, including myocardial infarction and ischemicstroke, especially in light of its unique cost-effectiveness andwidespread availability (reviewed by Gorelick & Weisman, Stroke. 2005August;36(8): 1801-7. Epub 2005 Jul. 14). In the secondary prevention ofcardiovascular, cerebrovascular, and ischemic events, the evidencesupports that the benefits of aspirin treatment significantly outweighthe risk of a major hemorrhage.

Attempts have been made to design multivitamin supplements specificallyfor heart health. Examples include U.S. Pat. No. 5,770,215, whichrelates to a multivitamin composition containing various vitamins,minerals, and acetylsalicylic acid, U.S. Pat. No. 5,948,443, whichpertains to an acetylsalicylic acid and micronutrient supplement, U.S.Pat. No. 6,914,073 which relates to a composition containing a highlevel of Vitamin E in encapsulated form, U.S. Pat. No. 6,953,593, whichpertains to a microencapsulation process or a sustained releaseformulation for oral delivery with a microencapsulated core material,International Patent Publication WO 98/41195, which encompasses anutritional supplement containing at least one flavonoid and folic acidor folate, International Patent Publication WO 03/030818 and relatedU.S. patent application Ser. No. 10/264,205 and Ser. No. 10/864,149,which pertain to active agent compositions using liposome beads andInternational Patent Publication No. WO 03/020260 and related U.S.patent application Ser. No. 11/141,085 and Ser. No. 10/234,002, whichpertain to compositions comprising at least one arginine compound orconjugate thereof and at least one member selected from the groupconsisting of high molecular weight aliphatic alcohol and methyl donorcofactor and conjugates thereof and methods of using the same.

There is a need for formulations with a low dose of aspirin withsupplements to limit gastro-intestinal toxicity to preventcardiovascular disease.

Citation or identification of any document in this application is not anadmission that such document is available as prior art to the presentinvention.

SUMMARY OF THE INVENTION

The invention is based, in part, on the Applicants' discovery that acombination of low dose aspirin and dietary supplements that may controlcholesterol or blood pressure levels.

The invention is based upon a formulation which may comprise, consistessentially of or consist of aspirin, vitamin B6, vitamin B12, folicacid, arginine and garlic. Advantageously, the aspirin is a low dose ofaspirin. The folic acid may also encompass folate. In anotheradvantageous embodiment, the arginine may be L-arginine, the garlic maybe a garlic extract, advantageously an aged garlic extract or an agedgarlic extract powder. In a particularly advantageous embodiment, theformulation may comprise, consist essentially of or consist of a lowdose of aspirin, vitamin B6, vitamin B12, folic acid or folate,L-arginine, aged garlic extract powder, or any combination thereof.

The invention also provides for a caplet or tablet which may comprise aformulation which may comprise, consist essentially of or consist ofaspirin, vitamin B6, vitamin B12, folic acid, arginine and garlic.Advantageously, the aspirin is a low dose of aspirin. The folic acid mayalso encompass folate. In another advantageous embodiment, the argininemay be L-arginine, the garlic may be a garlic extract, advantageously anaged garlic extract or an aged garlic extract powder. In a particularlyadvantageous embodiment, the caplet or tablet comprises a formulationmay comprise, consist essentially of or consist of a low dose ofaspirin, vitamin B6, vitamin B12, folic acid or folate, L-arginine, agedgarlic extract powder, or any combination thereof.

Advantageously, dosage per caplet or tablet of aspirin is 81 mg, vitaminB6 is 25 mg, vitamin B12 is 200 mcg, folic acid or folate is 600 mcg,arginine, advantageously L-arginine, is 200 mg and garlic,advantageously a garlic extract, an aged garlic extract or an agedgarlic extract powder, is 500 mg. The caplet or tablet of may furthercomprise cellulose, silica and magnesium stearate. In anotherembodiment, the caplet or tablet may further comprise calcium carbonate,carnauba wax, colloidal silicon dioxide, crospovidone, hypromellulose,lactose, magnesium stearate, maltodextrin, microcrystalline cellulose,pregelatinized starch, sodium starch glycolate, stearic acid, titaniumdioxide, tracetin, zinc stearate or any combination thereof. Preferably,the caplet or tablet does not contain gluten, preservatives, sugar,sodium, milk, yeast, artificial colors, artificial flavors or anycombination thereof.

Advantageously, the caplet or tablet may be enteric coated.

The present invention also provides for method of maintaining healthyblood pressure and cholesterol levels which may comprise administeringany of the above-described caplets or tablets which may comprise any oneof the above-described formulations to a patient in need of maintenanceof healthy blood pressure and cholesterol levels. In an advantageousembodiment, the caplet or tablet may be administered once per day.

It is noted that in this disclosure and particularly in the claimsand/or paragraphs, terms such as “comprises”, “comprised”, “comprising”and the like can have the meaning attributed to it in U.S. patent law;e.g., they can mean “includes”, “included”, “including”, and the like;and that terms such as “consisting essentially of” and “consistsessentially of” have the meaning ascribed to them in U.S. patent law,e.g., they allow for elements not explicitly recited, but excludeelements that are found in the prior art or that affect a basic or novelcharacteristic of the invention.

These and other embodiments are disclosed or are obvious from andencompassed by, the following Detailed Description.

DETAILED DESCRIPTION

The invention is based, in part, on the Applicants' discovery that acombination of low dose aspirin and dietary supplements that may controlcholesterol or blood pressure levels.

The invention is based upon a formulation which may comprise, consistessentially of or consist of aspirin, vitamin B6, vitamin B12, folicacid, arginine and garlic.

Aspirin includes, but is not limited to, all forms of acetylsalicylicacid including buffered aspirin, enteric coated aspirin, aspirin saltssuch as calcium acetylsalicylate, and mixtures of aspirin with acidacceptors any of which may be used in the formulation of the presentinvention. Advantageously, the aspirin is a low dose of aspirin.Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for theiranti-inflammatory, analgesic, and anti-pyretic effects, whereas low-doseaspirin (also an NSAID) is used for cardiovascular prophylaxis (reviewedby Laine, Rev Gastroenterol Disord. 2004;4 Suppl 4:S33-41). The mainconcern limiting use of these drugs is their gastrointestinal (GI)toxicity. GI side effects include ulcers (found at endoscopy in 15%-30%of patients using NSAIDs regularly), complications such as upper GIbleeding (annual incidence of 1.0%-1.5%), and development of upper GIsymptoms such as dyspepsia (occurring in up to 60% of patients takingNSAIDs).

The aspirin formulations as described in U.S. Pat. Nos. 6,967,212;6,960,357; 6,953,593; 6,881,860; 6,852,878; 6,825,208; 6,716,869;6,677,356; 6,673,831; 6,669,955; 6,656,482; 6,589,556; 6,585,995;6,576,256; 6,566,384; 6,559,133; 6,492,401; 6,491,949; 6,489,341;6,482,811; 6,407,135; 6,403,571; 6,399,079; 6,376,242; 6,310,088;6,309,669; 6,274,170; 6,251,852; 6,245,811; 6,235,311; 6,187,924;6,159,993; 6,102,254; 6,071,523; 6,040,147; 5,989,578; 5,916,910;5,881,926; 5,871,766; 5,846,959; 5,846,566; 5,811,547; 5,733,572;5,700,410; 5,292,512; 5,023,085; 4,885,287; 4,795,641; 4,559,329;4,327,725 and 4,256,108, the disclosures of which are incorporated byreference in their entireties, may be used in the present invention.

The term “low dose aspirin” is widely known to one of skill in the art.Low dose aspirin may generally refer to a daily aspirin dose less thanabout 200 mg, less than about 175 mg, less than about 150 mg, less thanabout 125 mg and more advantageously, less than about 100 mg per day.Advantageously, a low dose of aspirin is about 90 mg, about 85 mg, about84 mg, about 83 mg, about 82 mg and most advantageously about 81 mg.

B-vitamins, i.e. folate, vitamin B12, vitamin B6 and riboflavin, may beused in the formulations of the present invention. These B-vitamins areinvolved in homocysteine metabolism (reviewed by Strain et al., ProcNutr Soc. 2004 November;63(4):597-603). Homocysteine is a S-containingamino acid and its plasma concentrations can be raised by variousconstitutive, genetic and lifestyle factors, by inadequate nutrientstatus and as a result of systemic disease and various drugs.Hyperhomocysteinaemia is a modest independent predictor ofcardiovascular disease and stroke, but causality and the precisepathophysiological mechanism(s) of homocysteine action remain unproven.The predominant nutritional cause of raised plasma homocysteine in mosthealthy populations is folate insufficiency. Vitamin B12 and, to alesser extent, vitamin B6 are also effective at lowering plasmahomocysteine, especially after homocysteine lowering by folic acid inthose individuals presenting with raised plasma homocysteine. However,riboflavin supplementation appears to be effective at lowering plasmahomocysteine only in those individuals homozygous for the T allele ofthe C677T polymorphism of the methylenetetrahydrofolate reductase(MTHFR) gene. This gene codes for the MTHFR enzyme that producesmethyltetrahydrofolate, which, in turn, is a substrate for theremethylation of homocysteine by the vitamin B12-dependent enzymemethionine synthase. Individuals with the MTHFR 677TT genotype aregenetically predisposed to elevated plasma homocysteine, and in mostpopulations have a markedly higher risk of cardiovascular disease.

The nutritional status and plasma concentrations of some group Bvitamins, namely vitamin B6, vitamin B12 and folic acid, have recentlyemerged as inverse correlates of cardiovascular risk, and severalexperimental and clinical studies, these latter mostly retrospective andcase-control studies, indicate a defect of such vitamins as capable ofpromoting the progression of atherosclerosis (reviewed by Granieri etal., Ital Heart J Suppl. 2005 January;6(1):1-16). Since all thesevitamins are implicated in homocysteine metabolism, and sincehomocysteine has a well-recognized relationship with cardiovascularrisk, the simplest hypothesis to explain the relationship of vitamin B6,vitamin B12 and folic acid on the one hand, and cardiovascular risk onthe other is that this relationship is mediated by plasma levels ofhomocysteine. The most convincing literature data for the existence of arelationship with cardiovascular risk are for vitamin B6 and folic acid.These vitamins, however, have also a series of in vitro effectsindicating a direct antiatherogenic action, and the results of severalclinical studies, especially for vitamin B6, indicate an inverserelationship with cardiovascular risk at least in part independent ofhomocysteinemia. A further confirmation of these data is important todevise future intervention strategies in primary and secondaryprophylaxis of atherosclerotic vascular disease.

Vitamin B6 encompasses pyridoxine hydrochloride in all physiologicallyacceptable forms which may be used in the formulation of the presentinvention. The vitamin B6 formulations as described in U.S. Pat. Nos.6,953,588; 6,933,291; 6,921,754; 6,845,777; 6,814,983; 6,770,663;6,770,307; 6,669,955; 6,579,899; 6,565,891; 6,551,627; 6,548,483;6,514,544; 6,441,038; 6,420,342; 6,407,141; 6,369,041; 6,361,800;6,338,862; 6,323,188; 6,322,504; 6,299,896; 6,291,533; 6,274,170;6,197,309; 6,133,318; 6,133,317; 6,121,249; 6,048,846; 5,993,866;5,985,339; 5,977,073; 5,976,568; 5,972,382; 5,948,443; 5,925,377;5,922,704; 5,885,976; 5,397,786; 5,332,579; 5,308,627 and 5,084,482, thedisclosures of which are incorporated by reference in their entireties,may be used in the present invention. Brands of vitamin B6 which may beused in the formulation of the present invention include, but are notlimited to, American Health Care, Basic Drugs, Bronson, Country Life,Energen, Golden Sun, Goldline, Health For Life, Hudson, Mason, Myers,Nat Rul Health, Natural Wealth, Nature Made, Natures Blend, Nature'sBounty, Natures Life, Natures Naturals, Natures Way, Natures Wonder(Nwndr), Now, Nutri Plus, Optimum, Pharma Pure, Private Label, Radiance,Rexall, Rexall Premium, Rugby, Schiff, Sentinel, Solaray, Solgar,Sundown, Super Drugs, Synergy Plus, Thompson, Tidyman, Twenty FirstCentury, Twinlab, Ultra Herbs, Windmill, and Your Life.

Vitamin B12 encompasses cyanocobalamin in all physiologically acceptableforms which may be used in the formulation of the present invention. Thevitamin B12 formulations as described in U.S. Pat. Nos. 6,953,588;6,933,291; 6,921,754; 6,845,777; 6,814,983; 6,770,307; 6,726,647;6,669,955; 6,596,701; 6,565,891; 6,551,629; 6,551,627; 6,548,483;6,514,544; 6,441,038; 6,420,342; 6,361,800; 6,338,862; 6,323,188;6,316,024; 6,299,896; 6,291,533; 6,274,170; 6,121,249; 6,056,973;6,048,846; 5,985,339; 5,976,568; 5,972,382; 5,948,443; 5,925,377;5,840,880; 5,834,626; 5,811,299; 5,698,232; 5,332,579; 5,308,627 and5,084,482, the disclosures of which are incorporated by reference intheir entireties, may be used in the present invention. Brands ofvitamin B12 which may be used in the formulation of the presentinvention include, but are not limited to, American Health Care, BasicDrugs, Basic Organics, Biochem, Bricker Labs, Bronson, Centrum, CountryLife, Damiana, Douglass Labs, Dowmor, Energen, Enzymatic Therapy, Fosfo,Generic, Golden Sun, Goldline, Health For Life, Health Tech, Hudson, I LX, Jarrow, Life Time, Mason, Nat Rul Health, Natural Wealth, NatureMade, Natures Blend, Nature's Bounty, Natures Life, Natures Naturals,Natures Plus, Natures Way, Natures Wonder (Nwndr), No Shot, Now, NutriPlus, Nutrimax Plus, Optimum, Pharma Pure, Phytopharmica, Private Label,Pro Biotiks, Radiance, Rexall, Rexall Premium, Rugby, Schiff, Sentinel,Solaray, Solgar, Source Naturals, Sundown, Super Drugs, Synergy Plus,Thompson, Tidyman, Twenty First Century, Twinlab, Ultra Herbs, Windmilland Your Life.

Folic acid encompasses folate in all physiologically acceptable formsusually free folic acid which may be used in the formulation of thepresent invention. The folic acid or folate formulations as described inU.S. Pat. Nos. 6,974,841; 6,949,537; 6,939,860; 6,933,291; 6,930,099;6,921,754; 6,914,073; 6,912,492; 6,911,438; 6,899,905; 6,881,752;6,881,419; 6,866,877; 6,863,904; 6,846,501; 6,845,777; 6,835,402;6,833,243; 6,827,954; 6,814,983; 6,794,375; 6,790,827; 6,790,462;6,777,237; 6,776,976; 6,774,111; 6,746,678; 6,733,764; 6,726,943;6,720,015; 6,716,462; 6,703,371; 6,693,129; 6,693,094; 6,673,831;6,669,955; 6,660,293; 6,646,013; 6,642,277; 6,630,160; 6,624,148;6,605,646; 6,596,701; 6,593,101; 6,583,152; 6,579,544; 6,576,666;6,576,256; 6,569,445; 6,565,891; 6,551,629; 6,548,483; 6,544,994;6,544,547; 6,537,976; 6,528,496; 6,528,259; 6,524,619; 6,521,247;6,514,544; 6,511,675; 6,500,459; 6,475,518; 6,471,968; 6,441,038;6,436,431; 6,420,342; 6,403,129; 6,376,549; 6,369,041; 6,361,800;6,352,713; 6,338,862; 6,329,162; 6,323,189; 6,323,188; 6,322,504;6,316,04; 6,316,024; 6,315,978; 6,299,925; 6,299,896; 6,297,224;6,291,533; 6,274,170; 6,270,774; 6,267,987; 6,265,391; 6,251,857;6,248,375; 6,245,797; 6,245,360; 6,218,120; 6,210,686; 6,207,651;6,207,190; 6,203,818; 6,191,133; 6,190,693; 6,156,355; 6,150,168;6,129,918; 6,127,370; 6,121,249; 6,117,872; 6,099,854; 6,086,910;6,074,821; 6,056,973; 6,054,128; 6,051,260; 6,048,846; 6,042,849;6,039,978; 6,033,884; 6,008,221; 5,994,109; 5,993,866; 5,985,665;5,985,339; 5,977,073; 5,976,568; 5,976,548; 5,972,382; 5,962,062;5,962,030; 5,962,020; 5,948,443; 5,922,704; 5,885,976; 5,849,338;5,820,847; 5,811,547; 5,807,586; 5,795,873; 5,770,215; 744,161;5,700,410; 5,691,325; 5,691,324; 5,688,488; 5,654,011; 5,569,477;5,563,126; 5,538,734; 5,536,506; 5,518,730; 5,470,846; 5,416,016;5,340,603; 5,132,113; 5,059,595; 4,557,934 and 4,058,122, thedisclosures of which are incorporated by reference in their entireties,may be used in the present invention. Brands of folic acid which may beused in the formulation of the present invention include, but are notlimited to, Basic Drugs, Basic Organics, Bronson, Centrum, Country Life,Cvc, Energen, Goldline, Health For Life, Landau, Mason, Mutual Drug,Natrol, Natural Wealth, Nature Made, Natures Blend, Nature's Bounty,Natures Life, Natures Naturals, Natures Plus, Natures Way, NaturesWonder (Nwndr), Now, Nutri Plus, Olay, Pharma Pure, Private Label,Radiance, Rainbow Light, Rexall, Rexall Premium, Rugby, Schiff,Sentinel, Solaray, Solgar, Source Naturals, Sundown, Superior HealthNutrition, Synergy Plus, Twenty First Century, Twinlab, Ultra Herbs,Windmill and Your Life.

In another embodiment, brands of a mixture of folic acid, vitamin B6 andvitamin B12 which may be used in the formulation of the presentinvention include, but are not limited to, Folgard, Mason and Sundown.

Any form of arginine may be used in the formulation of the presentinvention. In another advantageous embodiment, the arginine may beL-arginine. Oral treatment with L-arginine improves endothelialdysfunction in hypertensives and lowers the blood pressure (reviewed byBolad & Delafontaine, Curr Opin Cardiol. 2005 July; 20(4): 270-4). Thereis also increasing interest in agentia combining the property ofupregulating NO-synthase (e.g. L-arginine) and restoring the balancebetween NO and free radicals (e.g. tetrahydrobiopterin) (reviewed byMoens et al., Int J Cardiol. 2005 Apr.20;100(2):179-90). One of suchagents could be folic acid. Furthermore, L-arginine, the substrate forNO synthesis, and the anti-oxidants ascorbate and alpha-tocopherol, areable to increase NO synthesis and bioavailability respectively (see,e.g., Woodman, Expert Opin Pharmacother. 2001 November;2(11):1765-75).

The arginine formulations as described in U.S. Pat. Nos. 6,953,593;6,911,455; 6,896,899; 6,869,973; 6,825,185; 6,797,705; 6,740,327;6,706,724; 6,693,122; 6,656,966; 6,649,629; 6,620,821; 6,617,359;6,548,483; 6,544,994; 6,528,507; 6,524,593; 6,495,530; 6,471,997;6,451,850; 6,444,816; 6,420,342; 6,417,207; 6,395,299; 6,369,067;6,342,481; 6,335,023; 6,284,277; 6,255,296; 6,245,811; 6,159,485;6,127,414; 6,054,453; 6,033,654; 6,004,933; 5,968,983; 5,906,987;5,886,041; 5,883,128; 5,811,547; 5,795,574; 5,750,572; 5,747,514;5,733,572; 5,702,688; 5,643,964; 5,543,430; 5,187,183; 5,073,547;4,920,098; 4,631,283 and 4,452,735, the disclosures of which areincorporated by reference in their entireties, may be used in thepresent invention.

Garlic and its preparations have been widely recognized as agents forprevention and treatment of cardiovascular and other metabolic diseases,atherosclerosis, hyperlipidemia, thrombosis, hypertension and diabetes(reviewed by Banerjee & Maulik, Nutr J. 2002 Nov. 19;1:4). Oxidativemodification of DNA, proteins and lipids by reactive oxygen species(ROS) plays a role in aging and disease, including cardiovascular,neurodegenerative and inflammatory diseases and cancer (reviewed byBorek, J Nutr. 2001 March;131(3s):1010S-5S). Extracts of fresh garlicthat are aged over a prolonged period to produce aged garlic extract(AGE) contain antioxidant phytochemicals that prevent oxidant damage.These include unique water-soluble organosulfur compounds, lipid-solubleorganosulfur components and flavonoids, notably allixin and selenium.Long-term extraction of garlic (up to 20 mo) ages the extract, creatingantioxidant properties by modifying unstable molecules with antioxidantactivity, such as allicin, and increasing stable and highly bioavailablewater-soluble organosulfur compounds, such as S-allylcysteine andS-allylmercaptocysteine. AGE exerts antioxidant action by scavengingROS, enhancing the cellular antioxidant enzymes superoxide dismutase,catalase and glutathione peroxidase, and increasing glutathione in thecells. AGE inhibits lipid peroxidation, reducing ischemic/reperfusiondamage and inhibiting oxidative modification of LDL, thus protectingendothelial cells from the injury by the oxidized molecules, whichcontributes to atherosclerosis. AGE inhibits the activation of theoxidant-induced transcription factor, nuclear factor (NF)-kappa B, whichhas clinical significance in human immunodeficiency virus geneexpression and atherogenesis. AGE protects DNA against freeradical—mediated damage and mutations, inhibits multistep carcinogenesisand defends against ionizing radiation and UV-induced damage, includingprotection against some forms of UV-induced immunosuppression. AGE mayhave a role in protecting against loss of brain function in aging andpossess other antiaging effects, as suggested by its ability to increasecognitive functions, memory and longevity in a senescence-acceleratedmouse model. AGE has been shown to protect against the cardiotoxiceffects of doxorubicin, an antineoplastic agent used in cancer therapyand against liver toxicity caused by carbon tetrachloride (an industrialchemical) and acetaminophen, an analgesic. Substantial experimentalevidence shows the ability of AGE to protect against oxidant-induceddisease, acute damage from aging, radiation and chemical exposure, andlong-term toxic damage. Although additional observations are warrantedin humans, compelling evidence supports the beneficial health effectsattributed to AGE, i.e., reducing the risk of cardiovascular disease,stroke, cancer and aging, including the oxidant-mediated brain celldamage that is implicated in Alzheimer's disease.

Any form of garlic which may be used in the formulation of the presentinvention The garlic may be a garlic extract, advantageously an agedgarlic extract or an aged garlic extract powder. Garlic has many otherhealth benefits beyond cholesterol: the herb also fights cancer andgreatly enhances immune system function. The garlic may be a garlicsupplement, advantageously an aged garlic supplement (e.g., availablefrom Kyolic). In a preferred embodiment, the aged garlic extract is AgedGarlic Extract™ (bulb).

The garlic formulations as described in U.S. Pat. Nos. 6,953,593;6,949,264; 6,932,989; 6,930,099; 6,866,864; 6,858,398; 6,692,789;6,689,588; 6,630,160; 6,620,440; 6,579,543; 6,555,134; 6,440,464;6,423,742; 6,379,714; 6,326,031; 6,309,676; 6,197,309; 6,171,635;6,156,355; 6,129,918; 6,048,846; 5,976,568; 5,976,549; 5,948,443;5,883,086; 5,641,533 and 5,626,901, the disclosures of which areincorporated by reference in their entireties, may be used in thepresent invention.

In a particularly advantageous embodiment, the formulation may comprise,consist essentially of or consist of a low dose of aspirin, vitamin B6,vitamin B12, folic acid or folate, L-arginine, aged garlic extractpowder, or any combination thereof.

The compounds of the present invention are advantageously useful inpreventing or treating cardiovascular diseases, such as, but not limitedto, atherosclerotic vascular disease, hypertension, heart failure,pulmonary hypertension and renal diseases. Advantageously, the compoundsof the present invention provides a method for maintaining healthy bloodpressure and cholesterol levels which may comprise administering any ofthe above-described caplets or tablets which may comprise any one of theabove-described formulations to a patient in need of maintenance ofhealthy blood pressure and cholesterol levels. In an advantageousembodiment, the caplet or tablet may be administered once per day.

Keeping cholesterol and blood pressure levels within a healthy rangehelps control two of the key risk factors for heart disease. There aretwo main types of cholesterol in the body. One type, named HDL forhigh-density lipoprotein is known as the “good” cholesterol, while theother type, named LDL for low-density lipoprotein, is known as the “bad”cholesterol. LDL (the “bad” type) can cause a buildup of fatty deposits,or plaque, that can clog arteries and make the heart work harder. Incontrast, HDL (the “good” type), carries LDL away from the arteries,lowering the risk of heart disease. High blood pressure can creep up onan individual and become a problem without the individual knowing it,which is why it is sometimes referred to as the “silent killer.” Highblood pressure can develop when arteries are narrowed, making it harderfor blood to flow through them. The result places a strain on the bloodvessels and is a reason why high blood pressure can lead to heartdisease. Without being bound by theory, the formulation of the presentinvention may protect the heart by keeping blood flowing freely.

When administered to a patient, a compound of the invention ispreferably administered as component of a composition that optionallycomprises a pharmaceutically acceptable vehicle The presentcompositions, which comprise a compound of the invention, are preferablyadministered orally. The compositions of the invention may also beadministered by any other convenient route, for example, by infusion orbolus injection, by absorption through epithelial or mucocutaneouslinings (e.g., oral mucosa, rectal, and intestinal mucosa, etc.) and maybe administered together with another biologically active agent.Administration can be systemic or local. Various delivery systems areknown, e.g., encapsulation in liposomes, microparticles, microcapsules,capsules, etc., and can be used to administer the compounds of theinvention.

In certain embodiments, the present compositions may comprise one ormore compounds of the invention.

Methods of administration include but are not limited to intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural, oral, sublingual, intranasal, intracerebral, intravaginal,transdermal, rectally, by inhalation, or topically, particularly to theears, nose, eyes, or skin. The mode of administration is left to thediscretion of the practitioner. In most instances, administration willresult in the release of a compound of the invention into thebloodstream.

In an advantageous embodiment, the administration is oral.

In an advantageous embodiment, the composition is enteric coated toprevent dissolution in the stomach. Advantageously, there is slowdissolution of the active substance until the tablet reaches thegastrointestinal tract. In a preferred embodiment, the compounds of thepresent invention are rapidly dispersed in the gastrointestinal tract.

In a less preferred embodiment, the compounds of the invention can bedelivered in a vesicle, in particular a liposome (see Langer, 1990.Science 249:1527-1533; Treat et al, in Liposomes in the Therapy ofInfectious Disease and Cancer, Lopez-Berestein and Fidler (eds.), Liss,N.Y., pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; seegenerally ibid).

In yet another less preferred embodiment, the compounds of the inventioncan be delivered in a controlled release system (see, e.g., Goodson, inMedical Applications of Controlled Release, supra, vol. 2, pp. 115-138(1984)). Other controlled-release systems discussed in the review byLanger, 1990, Science 249:1527-1533) may be used. In one embodiment, apump may be used (see Langer, supra; Sefton, 1987, CRC Crit. Ref.Biomed. Eng. 14:201; Buchwald et al., 1980, Surgery 88:507 Saudek etal., 1989, N. Engl. J. Med. 321:574). In another embodiment, polymericmaterials can be used (see Medical Applications of Controlled Release,Langer and Wise (eds.), CRC Pres., Boca Raton, Fla. (1974); ControlledDrug Bioavailability, Drug Product Design and Performance, Smolen andBall (eds.), Wiley, N.Y. (1984); Ranger and Peppas, 1983, J. Macromol.Sci. Rev. Macromol. Chem. 23:61; see also Levy et al., 1985, Science228:190; During et al., 1989, Ann. Neurol. 25:351; Howard et al., 1989,J. Neurosurg. 71:105). In yet another embodiment, a controlled-releasesystem can be placed in proximity of a target of a compound of theinvention, thus requiring only a fraction of the systemic dose.

The present compositions can optionally comprise a suitable amount of apharmaceutically acceptable vehicle so as to provide the form for properadministration to the patient.

In a specific embodiment, the tern “pharmaceutically acceptable” meansapproved by a regulatory agency of the Federal or a state government orlisted in the U.S. Pharmacopeia or other generally recognizedpharmacopeia for use in animals, mammals, and more particularly inhumans. The term “vehicle” refers to a diluent, adjuvant, excipient, orcarrier with which a compound of the invention is administered. Suchpharmaceutical vehicles can be liquids, such as water and oils,including those of petroleum, animal, vegetable or synthetic origin,such as peanut oil, soybean oil, mineral oil, sesame oil and the like.The pharmaceutical vehicles can be saline, gum acacia, gelatin, starchpaste, talc, keratin, colloidal silica, urea, and the like. In addition,auxiliary, stabilizing, thickening. lubricating and coloring agents maybe used. When administered to a patient, the pharmaceutically acceptablevehicles are preferably sterile. Water is a preferred vehicle when thecompound of the invention is administered intravenously. Salinesolutions and aqueous dextrose and glycerol solutions can also beemployed as liquid vehicles, particularly for injectable solutions.Suitable pharmaceutical vehicles also include excipients such as starch,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, sodium stearate, glycerol monostearate, talc, sodium chloride,dried skim milk, glycerol, propylene, glycol, water, ethanol and thelike. The present compositions, if desired, can also contain minoramounts of wetting or emulsifying agents, or buffering agents.

The present compositions can take the form of solutions, suspensions,emulsion, tablets, pills, pellets, capsules, capsules containingliquids, powders, sustained-release formulations, suppositories,emulsions, aerosols, sprays, suspensions, or any other form suitable foruse. In one embodiment, the pharmaceutically acceptable vehicle is acapsule (see e.g., U.S. Pat. No. 5,698,155). Other examples of suitablepharmaceutical vehicles are described in Remington's PharmaceuticalSciences, Alfonso R. Gennaro ed., Mack Publishing Co. Easton, Pa., 19thed., 1995, pp. 1447 to 1676, incorporated herein by reference.

Advantageously, the composition is administered in the form of a capletor a tablet. A tablet generally refers to a small solid pill containinga measured medicinal dose, usually intended to be taken orally. A capletgenerally refers to a tablet of medicine taken orally. The terms tabletand caplet may be used interchangeably.

In a preferred embodiment, the compounds of the invention are formulatedin accordance with routine procedures as a pharmaceutical compositionadapted for oral administration to human beings. Compositions for oraldelivery may be in the form of tablets, lozenges, aqueous or oilysuspensions, granules, powders, emulsions, capsules, syrups, or elixirs,for example. Orally administered compositions may contain one or moreagents, for example, sweetening agents such as fructose, aspartame orsaccharin; flavoring agents such as peppermint, oil of wintergreen, orcherry; coloring agents; and preserving agents, to provide apharmaceutically palatable preparation. Moreover, where in tablet orpill form, the compositions can be coated to delay disintegration andabsorption in the gastrointestinal tract thereby providing a sustainedaction over an extended period of time. Selectively permeable membranessurrounding an osmotically active driving compound are also suitable fororally administered compositions. In these later platforms, fluid fromthe environment surrounding the capsule is imbibed by the drivingcompound, which swells to displace the agent or agent compositionthrough an aperture. These delivery platforms can provide an essentiallyzero order delivery profile as opposed to the spiked profiles ofimmediate release formulations. A time delay material such as glycerolmonostearate or glycerol stearate may also be used. Oral compositionscan include standard vehicles such as mannitol, lactose, starch,magnesium stearate, sodium saccharine, cellulose, magnesium carbonate,etc. Such vehicles are preferably of pharmaceutical grade. Typically,compositions for intravenous administration comprise sterile isotonicaqueous buffer. Where necessary, the compositions may also include asolubilizing agent.

The amount of a compound of the invention that will be effective in thetreatment of a particular disorder or condition disclosed herein willdepend on the nature of the disorder or condition, and can be determinedby standard clinical techniques. In addition, in vitro or in vivo assaysmay optionally be employed to help identify optimal dosage ranges. Theprecise dose to be employed will also depend on the route ofadministration, and the seriousness of the disease or disorder, andshould be decided according to the judgment of the practitioner and eachpatient's circumstances. However, suitable dosage ranges for oraladministration are generally about 0.001 milligram to about 200milligrams of a compound of the invention or a pharmaceuticallyacceptable salt thereof per kilogram body weight per day. In specificpreferred embodiments of the invention, the oral dose is about 0.01milligram to about 100 milligrams per kilogram body weight per day, morepreferably about 0.1 milligram to about 75 milligrams per kilogram bodyweight per day, more preferably about 0.5 milligram to 5 milligrams perkilogram body weight per day. The dosage amounts described herein referto total amounts administered; that is, if more than one compound of theinvention is administered, or if a compound of the invention isadministered with a therapeutic agent, then the preferred dosagescorrespond to the total amount administered. Oral compositionspreferably contain about 10% to about 95% active ingredient by weight.

The dosage of aspirin may be less than about 500 mg, less than about 450mg, less than about 400 mg, less than about 350 mg, less than about 300mg, less than about 250 mg, less than about 200 mg, less than about 175mg, less than about 150 mg, less than about 125 mg and moreadvantageously, less than about 100 mg per day. Advantageously, a lowdose of aspirin is about 90 mg, about 85 mg, about 84 mg, about 83 mg,about 82 mg and most advantageously about 81 mg. The dosage of aspirinmay also be about 80 mg, about 75 mg, about 70 mg, about 65 mg, about 60mg, about 55 mg, about 50 mg, about 45 mg, about 40 mg, about 35 mg,about 30 mg, about 25 mg, about 20 mg, about 15 mg or about 10 mg.

The dosage of vitamin B6 may be about 100 mg, about 95 mg, about 90 mg,about 85 mg, about 80 mg, about 75 mg, about 70 mg, about 65 mg, about60 mg, about 55 mg, about 50 mg, about 45 mg, about 40 mg, about 35 mg,about 30 mg, about 29 mg, about 28 mg, about 27 mg, about 26 mg,advantageously about 25 mg, about 24 mg, about 23 mg, about 22 mg, about21 mg, about 20 mg, about 15 mg, about 10 mg or about 5 mg.

The dosage of vitamin B12 may be about 1000 mcg, about 950 mg, about 900mcg, about 850 mcg, about 800 mcg, about 750 mcg, about 700 mcg, about650 mcg, about 600 mcg, about 550 mcg, about 500 mcg, about 450 mcg,about 400 mcg, about 350 mcg, about 300 mcg, about 250 mcg, about 240mcg, about 230 mcg, about 220 mcg, about 210 mg, advantageously about200 mcg, about 190 mcg, about 180 mcg, about 170 mcg, about 160 mcg,about 150 mcg, about 100 mcg or about 50 mcg.

The dosage of folic acid or folate may be about 3000 mcg, mcg, about2900 mcg, about 2800 mcg, about 2700 mcg, about 2600 mcg, about 2500mcg, about 2400 mcg, about 2300 mcg, about 2200 mcg, about 2100 mcg,about 2000 mcg, about 1900 mcg, about 1800 mcg, about 1700 mcg, about1600 mcg, about 1500 mcg, mcg, about 1400 mcg, about 1300 mcg, about1200 mcg, about 1100 mcg, about 1000 mcg, about 950 mg, about 900 mcg,about 850 mcg, about 800 mcg, about 750 mcg, about 700 mcg, about 690mcg, about 680 mcg, about 670 mcg, about 660 mcg, about 650 mcg, about640 mcg, about 630 mcg, about 620 mcg, about 610 mcg, aboutadvantageously about 600 mcg, about 590 mcg, about 580 mcg, about 570mcg, about 560 mcg, about 550 mcg, about 540 mcg, about 530 mcg, about520 mcg, about 510 mcg, about 500 mcg, about 450 mcg, about 400 mcg,about 350 mcg, about 300 mcg, about 250 mcg, about 200 mcg, about 150mcg or about 100 mcg.

The dosage of arginine may be about 1000 mg, about 950 mg, about 900 mg,about 850 mg, about 800 mg, about 750 mg, about 700 mg, about 650 mg,about 600 mg, about 550 mg, about 500 mg, about 450 mg, about 400 mg,about 350 mg, about 300 mg, about 250 mg, about 240 mg, about 230 mg,about 220 mg, about 210 mg, advantageously about 200 mg, about 190 mg,about 180 mg, about 170 mg, about 160 mg, about 150 mg, about 100 mg orabout 50 mg.

The dosage of garlic may be about 3000 mg, mg, about 2900 mg, about 2800mg, about 2700 mg, about 2600 mg, about 2500 mg, about 2400 mg, about2300 mg, about 2200 mg, about 2100 mg, about 2000 mg, about 1900 mg,about 1800 mg, about 1700 mg, about 1600 mg, about 1500 mg, mg, about1400 mg, about 1300 mg, about 1200 mg, about 1100 mg, about 1000 mg,about 950 mg, about 900 mg, about 850 mg, about 800 mg, about 750 mg,about 700 mg, about 600 mg, about 590 mg, about 580 mg, about 570 mg,about 560 mg, about 550 mg, about 540 mg, about 530 mg, about 520 mg,about 510 mg, advantageously about 500 mg, about 490 mg, about 480 mg,about 470 mg, about 460 mg, about 450 mg, about 440 mg, about 430 mg,about 420 mg, about 410 mg, about 400 mg, about 350 mg, about 300 mg,about 250 mg, about 200 mg, about 150 mg or about 100 mg.

Advantageously, dosage per caplet or tablet of aspirin is about 81 mg,vitamin B6 is about 25 mg, vitamin B12 is about 200 mcg, folic acid orfolate is about 600 mcg, arginine, advantageously L-arginine, is about200 mg and garlic, advantageously a garlic extract, an aged garlicextract or an aged garlic extract powder, is about 500 mg.

The caplet or tablet of may further comprise cellulose, silica andmagnesium stearate. In another embodiment, the caplet or tablet mayfurther comprise calcium carbonate, carnauba wax, colloidal silicondioxide, crospovidone, hypromellulose, lactose, magnesium stearate,maltodextrin, microcrystalline cellulose, pregelatinized starch, sodiumstarch glycolate, stearic acid, titanium dioxide, tracetin, zincstearate or any combination thereof. Preferably, the caplet or tabletdoes not contain gluten, preservatives, sugar, sodium, milk, yeast,artificial colors, artificial flavors or any combination thereof.

The invention also provides pharmaceutical packs or kits comprising oneor more vessels containing one or more compounds of the invention.Optionally associated with such container(s) can be a notice in the formprescribed by a governmental agency regulating the manufacture, use orsale of pharmaceuticals or biological products, which notice reflectsapproval by the agency of manufacture, use or sale for humanadministration. In a certain embodiment, the kit contains more than onecompound of the invention. In another embodiment, the kit comprises atherapeutic agent and a compound of the invention.

The compounds of the invention are preferably assayed in vitro and invivo, for the desired therapeutic or prophylactic activity, prior to usein humans. For example, in vitro assays can be used to determine whetherit is preferable to administer a compound of the invention alone or incombination with another compound of the invention and/or a therapeuticagent. Animal model systems can be used to demonstrate safety andefficacy.

Other methods will be known to the skilled artisan and are within thescope of the invention.

In certain embodiments of the present invention, a compound of theinvention can be used in combination therapy with at least one othertherapeutic agent. The compound of the invention and the therapeuticagent can act additively or, more preferably, synergistically. In apreferred embodiment, a composition comprising a compound of theinvention is administered concurrently with the administration ofanother therapeutic agent, which can be part of the same composition asor in a different composition from that comprising the compound of theinvention. In another embodiment, a composition comprising a compound ofthe invention is administered prior or subsequent to administration ofanother therapeutic agent. As many of the disorders for which thecompounds of the invention are useful in treating are chronic, in oneembodiment combination therapy involves alternating betweenadministering a composition comprising a compound of the invention and acomposition comprising another therapeutic agent, e.g., to minimize thetoxicity associated with a particular drug. The duration ofadministration of the compound of the invention or therapeutic agent canbe, e.g., one month, three months, six months, a year, or for moreextended periods. In certain embodiments, when a compound of theinvention is administered concurrently with another therapeutic agentthat potentially produces adverse side effects including, but notlimited to, toxicity, the therapeutic agent can advantageously beadministered at a dose that falls below the threshold at which theadverse side is elicited.

Having thus described in detail preferred embodiments of the presentinvention, it is to be understood that the invention defined by theabove paragraphs is not to be limited to particular details set forth inthe above description as many apparent variations thereof are possiblewithout departing from the spirit or scope of the present invention.

1. A formulation comprising aspirin, vitamin B6, vitamin B12, folicacid, arginine and garlic.
 2. The formulation of claim 1, wherein theaspirin is a low dose of aspirin, wherein the low dose aspirin is adaily aspirin dose less than about 200 mg.
 3. The formulation of claim1, wherein the folic acid is folate.
 4. The formulation of claim 1,wherein the arginine is L-arginine.
 5. A caplet or tablet comprising theformulation of claim
 1. 6. The caplet or tablet of claim 5, wherein adosage per caplet or tablet of aspirin is 81 mg, vitamin B6 is 25 mg,vitamin B12 is 200 mcg, folic acid is 600 mcg, arginine is 200 mg andgarlic is 500 mg.
 7. The caplet or tablet of claim 5 further comprisingcellulose, silica and magnesium stearate.
 8. The caplet or tablet ofclaim 5 further comprising calcium carbonate, carnauba wax, colloidalsilicon dioxide, crospovidone, hypromellulose, lactose, magnesiumstearate, maltodextrin, microcrystalline cellulose, pregelatinizedstarch, sodium starch, glycolate, stearic acid, titanium dioxide,tracetin, zinc stearate or any combination thereof.
 9. The caplet ortablet of claim 5 wherein the caplet or tablet does not contain gluten,preservatives, sugar, sodium, milk, yeast, artificial colors, artificialflavors or any combination thereof.
 10. The caplet or tablet of claim 5wherein the caplet or tablet is enteric coated.
 11. A method ofmaintaining healthy blood pressure and cholesterol levels comprisingadministering the caplet or tablet of claim 5 to a patient in need ofmaintenance of healthy blood pressure and cholesterol levels.
 12. Themethod of claim 11 wherein the caplet or tablet is administered once perday.